Diabetologia ( IF 8.4 ) Pub Date : 2021-12-24 , DOI: 10.1007/s00125-021-05631-z Jarno L T Kettunen 1, 2, 3, 4 , Elina Rantala 5 , Om P Dwivedi 2 , Bo Isomaa 1 , Leena Sarelin 1 , Paula Kokko 1, 2, 4 , Liisa Hakaste 1, 2, 3, 4 , Päivi J Miettinen 6, 7 , Leif C Groop 2, 8 , Tiinamaija Tuomi 1, 2, 3, 4, 8
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Aims/hypothesis
Systematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum.
Methods
We conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT.
Results
Half of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17–35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m2 units of BMI, p=2.2 × 10−4, using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 μmol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 μmol/l, p=3.1 × 10−5).
Conclusions/interpretation
The most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes.
Graphical abstract
中文翻译：
关于 HNF1A-MODY 最常见因果变异的表型后果的多代研究
目标/假设
很少有关于 HNF1A-MODY 变异的表型后果的系统研究。我们的目的是评估单个HNF1A变体携带者的表型以及影响临床谱的遗传和临床因素。
方法
我们通过比较HNF1A p.(Gly292fs) 变异的杂合子携带者与非携带者亲属进行了一项基于家庭的多代研究，无论其糖尿病状态如何。在二十多年的时间里，来自 12 个家庭的 145 名携带者和 131 名非携带者参与了这项研究，其中 208 名至少接受了一次 OGTT。我们评估了 2 型糖尿病的多基因风险评分、糖尿病发病年龄和身体成分的测量，以及 OGTT 期间的血浆葡萄糖、血清胰岛素、胰岛素原、C 肽、胰高血糖素和 NEFA 反应。
结果
一半的携带者在 23 岁时仍然没有糖尿病，三分之一在 33 岁时，13% 甚至在 50 岁时。诊断时的中位年龄为 21 岁（IQR 17-35）。我们无法确定影响转换年龄的临床因素；性别、BMI、胰岛素敏感性或父母携带状态没有显着影响。然而，对于 2 型糖尿病的多基因风险评分每增加 1 个 SD 单位，诊断时的预测年龄减少了 3.2 岁。在OGTT期间，携带者的血糖水平高于非携带者，血清胰岛素和C肽水平低于非携带者。携带者也比非携带者更瘦（5.0 kg，p = 0.012，和 2.1 kg/m 2 单位的 BMI，p = 2.2 × 10 -4，使用第一次成人测量），并且可能是由于胰岛素缺乏，显示出更高的脂肪分解活性（空腹时 NEFA 的中位数为 621 与 441 μmol/l，p = 0.0039；OGTT 期间 120 分钟时为 117 与 64 μmol/ l, p =3.1 × 10 -5 )。
结论/解释
HNF1A-MODY 最常见的致病变异体 p.(Gly292fs) 不仅表现为高血糖和胰岛素缺乏，还表现为脂肪分解增加和成人 BMI 显着降低。血清胰岛素比 C 肽在携带者和非携带者之间的区别更大。相当比例的携带者在成年后发展为糖尿病。即使在患有单基因糖尿病的个体中，糖尿病的多基因风险也会改变糖尿病的发病年龄。
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